Many patients in clinical practice are unable to completely suppress viral replication with highly active antiretroviral therapy (HAART). Failure of HAART to fully suppress viral replication eventually leads to the emergence of highly resistant HIV and, in some cases, increasing levels of viral replication and decreasing CD4+ T cell counts. However, the level of drug-resistant viremia often remains below the pre-treatment set-point, even after highly resistant variants emerge. Recent data from our group suggest that several factors contribute to this reduced steady state viral load, including the findings that drug-resistant variants have reduced replicative capacity in vitro and pathogenic potential in vivo, and that patients who durably maintain low to moderate levels of drug-resistant plasma viremia often have high levels of HIV-specific CD4+ and CD8+ T cells. Based on these observations, we postulate that the emergence of a poorly fit, drug-resistant variant results in the generation and preservation of an effective HIV-specific CD4+ T cell response, and that this response contributes to the establishment of a lower steady state level of viremia. We are about to begin a pilot clinical study to test the hypothesis that aggressive antiretroviral treatment in patients with multi-drug resistant HIV-1 can result in the expansion of HIV-specific CD4+ and CD8+ T cell numbers and a reduced viral load set-point. As part of this clinical study, we will collect peripheral blood mononuclear cells. We are requesting funds in this R21 to determine the effect of treatment changes on the frequency of HIV-specific cells and the relationship between immunologic measures and change in viremia. Using cytokine flow cytometry, we will detect and enumerate CD4+ and CD8+ T cells, and we will measure both HIV-specific proliferation and cytokine production. Funding for the pilot clinical trial has been obtained from other sources; funding is requested in this proposal only for costs associated with the measurements of immunologic response to drug-resistant HIV-1.